|Year : 2018 | Volume
| Issue : 2 | Page : 412-416
Predictors of sustained virological response to therapy with pegylated interferon plus ribavirin in hepatitis C virus patients
Ehab A Abdelatty1, El-Sayed I El-Shayeb1, Ahmad G El-Feky2
1 Department of Internal Medicine, Faculty of Medicine, Menuofia University, Shibin El Kom, Egypt
2 Hepatology Center, Kafr El-Sheikh, Egypt
|Date of Submission||01-Oct-2016|
|Date of Acceptance||02-Jan-2017|
|Date of Web Publication||27-Aug-2018|
Ahmad G El-Feky
Department of Internal Medicine, Faculty of Medicine, Menuofia University, Shibin El Kom
Source of Support: None, Conflict of Interest: None
The aim of this study was to determine the factors that may affect the response to combined therapy of pegyated interferon (PEG-INF) and ribavirin (RBV) in chronic hepatitis C virus (HCV) Egyptian patients for achieving sustained virological response (SVR), which means negative PCR 12 weeks after end of treatment.
HCV is a global disease whose morbidity and mortality are increasing. HCV is a single-stranded RNA virus classified in the genus hepacivirus of the flaviviridae family, consisting out of 9600 nucleotides and stored inside the nucleocapsid. Six major HCV genotypes and over 70 subtypes have been identified. HCV-G4 is the most common genotype in Egypt.
Patient and methods
This study was carried out on 500 naive HCV-infected Egyptian patients attending Kafr El-Sheikh Liver Research Center for receiving combined antiviral therapy (PEG-INF and RBV) for 48 weeks. They were divided into two groups: group I, including 368 patients who had negative PCR 24 weeks after end of therapy (SVR); and group II, including 132 patients who had positive PCR 24 weeks after end of therapy (non-SVR).
We found that many factors either related to the virus as viral load or related to the host as normal serum albumin level, lower levels of serum transaminases, low bilharzial titre level, and low grade of liver fibrosis could be a good predictors of response to antiviral therapy in chronic HCV Egyptian patients achieving SVR.
Normal serum albumin, lower level of serum transaminases, low bilharzial titre, low grade of liver fibrosis, and low baseline serum viral load all are good predictors for achieving SVR in chronic HCV Egyptian patients treated with combined PEG-INF and RBV therapy.
Keywords: hepatitis C, interferon, predictors, sustained virological response
|How to cite this article:|
Abdelatty EA, El-Shayeb ESI, El-Feky AG. Predictors of sustained virological response to therapy with pegylated interferon plus ribavirin in hepatitis C virus patients. Menoufia Med J 2018;31:412-6
|How to cite this URL:|
Abdelatty EA, El-Shayeb ESI, El-Feky AG. Predictors of sustained virological response to therapy with pegylated interferon plus ribavirin in hepatitis C virus patients. Menoufia Med J [serial online] 2018 [cited 2018 Nov 16];31:412-6. Available from: http://www.mmj.eg.net/text.asp?2018/31/2/412/239735
| Introduction|| |
Hepatitis C virus (HCV) is a global disease whose morbidity and mortality are increasing. The WHO estimated that 3% of the world's population or ∼130–170 million people were chronically infected with HCV at the end of the 20th century, and that 2.4–4.7 million new infections are reported per year .
Some calculations suggest that mortality related to HCV infection (death from liver failure or hepatocellular carcinoma) will continue to increase over the next two decades . Egypt has the highest prevalence of antibodies to HCV in the world, estimated nationally to be 14.7%, and an estimated 9.8% are chronically infected .
HCV transmission is ongoing in Egypt, and incidence rates have been estimated at 2.4/1000 person-years (165 000 new infections annually) .
Concurrent HCV-genotype 4 infection and schistosomiasis result in a much more severe liver disease than that seen with either disease alone .
Combination therapy of pegylated interferon (PEG-INF) and ribavirin (RBV) has been previously recognized as a standard treatment for HCV infection . Unfortunately, this standard therapy produced a sustained virological response (SVR) in only 50% of HCV-infected patients. Clinical and histological findings may play a role in predicting response to standard PEG-INF/RBV therapy .
The primary aim of antiviral therapy in HCV patients was SVR, which has been defined as undetectable serum HCV RNA 12 weeks after completion of therapy .
Many host and viral factors influence SVR rate to combined interferon and RBV therapy. Viral factors include viral load and genotype, whereas host factors include age, sex, host immune status, , grading of necroinflammation, staging of fibrosis, HLA  ethnicity, and BMI .
In our study we aimed to determine factors that may affect the response to combined therapy of PEG-INF and RBV in chronic active HCV Egyptian patients.
| Patients and Methods|| |
This retrospective study was carried out on 500 naive HCV-infected Egyptian patients attending Kafr El-Sheikh Liver Research Center for receiving combined antiviral therapy (PEG-INF and RBV) for 48 weeks during the period between from January 2010 to January 2013. They were divided into two groups: group I, which included 368 patients who had negative PCR 24 weeks after end of therapy (SVR); and group II, which included 132 patients who had positive PCR 24 weeks after end of therapy (non-SVR). Our study was approved by the Ethical Committee of Menoufia Faculty of Medicine.
Patients with positive HCV antibodies by enzyme-linked immunosorbent assay, HCV RNA by PCR, and histological evidence of chronic HCV were included.
Following were the exclusion criteria: refusal to participate in the study, pregnant or breast feeding females, age less than 18 and more than 60, F4 on liver biopsy, history or other evidence of a medical condition associated with chronic liver disease other than chronic hepatitis C (e.g., hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, toxin exposure), severe concurrent medical disease (such as severe hypertension, heart failure, significant coronary heart disease, poorly controlled diabetes, and chronic obstructive pulmonary disease), major uncontrolled depressive illness, solid organ transplant (renal, heart, or lung), untreated thyroid disease, BMI more than 35, and known hypersensitivity to drugs used to treat HCV.
All patients were subjected to the following:
- Laboratory investigations, which included complete blood count, liver function tests [aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, serum bilirubin (total and direct), serum albumin, prothrombin time and activity], thyroid stimulating hormone, antinuclear antibody, α-feto protein, viral markers (HCV antibodies and hepatitis B surface antigen), and HCV-RNA PCR, These investigations were done in different laboratories using different instruments and machines according to each lab available to patient and all were accepted in our study
- Abdominal ultrasonography for the liver (size, border, hepatic veins, and echogenicity), splenic size, portal vein diameter, the presence of ascites, and other abdominal organs by using different types of ultrasound machines according to the related radiology center
- Liver biopsy, which was carried out by inserting a trucut needle through an intercostal space in the right mid axillary line during expiration using local anesthesia provided that the patient was cooperative and platelet count was more than 100 000 and that there was no bile duct obstruction, and prothrombin time was not more than 4 s above normal to detect the stage of fibrosis and necroinflammatory activity. These biopsies were taken after complete written consent from the patients, for histopathological grading and staging of hepatic fibrosis by an experienced pathologist using the Metavir scoring system.
Data were analyzed using the statistical program for the social science (SPSS), version 20.0 (IBM Corp. Released 2011. Armonk, NY). Quantitative data were expressed as mean ± SD. Qualitative data were expressed as frequency and percentage.
The following tests were done:
- Independent-samples t-test of significance was used when comparing between two means
- The χ2-test of significance was used to compare proportions between two qualitative parameters
- Pearson's correlation coefficient (r) test was used for correlating data
- Binary logistic regression was used to predict the outcome of categorical variable based on one or more predictor variables
- P value:
- P up to 0.05 was considered significant
- P up to 0.001 was considered as highly significant
- P value more than 0.05 was considered insignificant.
| Results|| |
The results of this study showed that the majority of studied patients achieving SVR were males 254 (69%). The mean age in the SVR group was 38.55 ± 9.19 years, and the mean BMI was 26.55 ± 2.97 kg/m 2 [Table 1] and [Table 2].
|Table 1: Comparison between the sustained virological response group and the nonsustained virological response group as regards demographic data|
Click here to view
|Table 2: Comparison between the sustained virological response group and the nonsustained virological response group as regards BMI|
Click here to view
The results of the present study indicated that there a was statistically significant difference between the SVR group and the non-SVR group as regards serum level of AST (P = 0.003), ALT (P = 0.022), normal albumin level (P = 0.033), normal thyroid stimulating hormone level (P = 0.047), and bilharzial titre (P < 0.01) [Table 3] and [Table 4]. Furthermore, there was a highly statistically significant difference between the SVR group and the non-SVR group as regards fibrosis stage (P < 0.001) [Table 5]. Our study also revealed a highly statistically significant difference between the SVR group and the non-SVR group as regards PCR viral load (P < 0.001), which was lower in the SVR group than in the non-SVR group (the mean level of PCR was 1 100 283 ± 6 330 063 and 1 401 736 ± 4 146 595, respectively) [Table 6].
|Table 3: Comparison between the sustained virological response group and the nonsustained virological response group as regards liver and renal function|
Click here to view
|Table 4 Comparison between the sustained virological response group and the nonsustained virological response group as regards fasting blood sugar, α-feto protein, thyroid stimulating hormone, and bilharzial titre|
Click here to view
|Table 5: Comparison between the sustained virological response group and the nonsustained virological response group as regards liver biopsy|
Click here to view
|Table 6: Comparison between the sustained virological response group and the nonsustained virological response group as regards PCR at baseline week 0 (viral load)|
Click here to view
In our study the patients with a low level of viremia at the start of treatment were more liable for achieving SVR: about 30.98% of patients compared with only 18.18% who could not achieve SVR in the same category, whereas the number of patients with intermediate viremia at the start of treatment who achieved SVR were about 58.97% compared with 62.12% in the same category who could not achieve SVR. Finally, patients with a high viral load accounted only about 10% of all patients who could achieve SVR [Table 7].
|Table 7: Comparison between the sustained virological response group and the nonsustained virological response group as regards viral load|
Click here to view
| Discussion|| |
This study revealed no significant difference regarding demographic parameters (age, sex, and BMI) between SVR and non-SVR groups. In contrast, Essmat et al.  found that males achieved early virological response and SVR than did females, which can be attributed to the high number of male patients in that study.
In our study, lower levels of liver transaminases (ALT and AST) were significant predictors of SVR, in comparison with other liver and kidney function tests, and this was in line with the results by Inees et al.  in their multivariate analysis.
In our study, hemoglobin percentage, white blood cells, and platelet count were not predictors of SVR; the same findings were reported by Inees et al. , apart from platelet count, especially in genotype 2 and 3, which was a predictor for SVR.
Low bilharzial titre in our study was a good predictor for SVR in comparison with the high titre in patients who did not achieve SVR; the same finding was reported by Khalil et al.  in their multivariate study on factors affecting SVR, as, interestingly, the frequency of responded patients with negative schistosomal antibodies (53.6%) was significantly higher than the frequency of nonresponded patients with negative schistosomal antibodies (29.7%) (P < 0.01).
The stage of fibrosis on liver biopsy in our study was a good predictor of SVR as patients with a lower fibrosis stage were more liable to achieve SVR than patients with advanced fibrosis. This was in agreement with Essmat et al.  and Torres et al. . Moreover, Ismail et al.  has reported the same findings for achieving SVR.
It was also reported that patients with HCV and cirrhosis have lower rates of SVR even in the absence of cirrhosis; the degree of response to treatment decreases with the increase of stage of fibrosis, as per De Carega .
Regarding DM there was no difference between diabetics and nondiabetics in achieving SVR, which can be attributed to the low numbers of diabetic patients in our study. In contrast, Elgouhari et al.  reported that HCV diabetics were more likely to have steatosis (P < 0.0001) and advanced fibrosis (P = 0.003).
Furthermore, significant adverse events were more common in HCV diabetics compared with HCV nondiabetics. In conclusion, DM was associated with impaired virological response to PEG-IFN/RBV in HCV patients. Adverse events during therapy were more frequent in diabetic compared with nondiabetic HCV patients.
Regarding PEG-INF (type and dose) and RBV dose, they had no significant role in the prediction of response and probability of achieving SVR. In contrast to the results of our study, Ascione et al.  reported a high SVR rate with PEG-IFN α-2a than with PEG-INF α-2b (68 vs. 45.4%).
In our study, a low serum baseline HCV-RNA viral level was a strong predictor for achieving SVR; similar findings were reported by Kamal et al. ,.
| Conclusion and Recommendation|| |
Our study revealed that normal serum albumin level, lower level of serum transaminases, low bilharzial titre, low grade of liver fibrosis, and low baseline serum viral load all are good predictors for achieving SVR in chronic HCV Egyptian patients treated with combined PEG-INF and RBV therapy. Hence, further studies are recommended about predictors of response to new oral interferon-free regimens antiviral therapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Essmat G, El Kassas M, Hassany M, Gamil ME, El Raziky M. How to optimize HCV therapy in genotype 4 patients. Liver Int 2013; 33:41–45.
Deuffic-Burban S, Poynard T, Sulkowski MS, Wong JB. Estimating the future health burden of chronic hepatitis C and human immunodeficiency virus infections in the United States. J Viral Hepat 2007; 14
Jacobson IM, Brown RS, Freilich B, Robert S, Afdhal N, Santoro J, et al.
Peg-interferon alfa-2b and weight-based or flat dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology 2007; 46
Miller FD, Abu-Raddad LJ. Evidence of intense ongoing endemic transmission of hepatitis C virus in Egypt. Proc Natl Acad Sci USA 2010; 107
Gad A, Tanaka E, Nooman Z, Serwah AH, Orii K, Shoair M, et al.
Relationship between hepatitis C virus infection and schistosomal liver disease: not simply an additive effect. J Gastroenterol 2001; 36
Mostafa A, Taylor S, El-Daly M, Bakr I, Arafa N, Thiers V, et al.
Is the hepatitis C virus epidemic over in Egypt? incidence and risk factors of new hepatitis C virus infections. Liver Int 2010; 31
Assad NY, Ehsan NA, Abdou AG, El Tahmody MA, El Sabaawy M, El Kholy S, et al.
The impact of clinicopathological parameters in predicting response to pegylated interferon and ribavirin in chronic hepatitis C patients. Menoufia Med J 2014; 27
Sabat R, Grutz G, Warszawska K, Kirsch S, Witte E, Wolk K, et al.
Biology of interleukin-10. Cytokine Growth Factor Rev 2010; 21
Fried MW, Shiffman ML, Reddy KR, Mitchell L, Smith C, Marinos G, et al.
Peg-interferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347
Kinzie JL, Naylor PH, Nathani MG, Peleman R, Lybic M, Janisse J, et al.
African Americans with genotype 1 treated with interferon for chronic hepatitis C have a lower end of treatment response than Caucasians. J Viral Hepat 2008; 8
Romero-Gomez M, Gonzalez-Escribano MF, Torres B, Barroso N, Montes-Cano MA, Aguilar-Reina J, et al.
HLA class I B44 is associated with sustained response to interferon and ribavirin therapy in patients with chronic hepatitis C. Am J Gastroenterol 2003; 98
Essmat GE, Maisa E, Rabab M, Wafaa AE, Waleed F, Dina IA. Predictors of complete early virological response to pegylated interferon and ribavirin in Egyptian patients with chronic hepatitis C genotype 4 and advances in infectious diseases. Adv Infect Dis 2013; 3
Inees HA, Hutchinson SJ, Allen S, Bhattacharyya D, Bramley P, Carman B, et al
. Ranking predictors of a sustained viral response for patients with chronic hepatitis C treated with pegylated interferon and ribavirin in Scotland. Eur J Gastroenterol Hepatol 2012; 24
Khalil A, Mohamed F, Nader A, Ryiad A. Predictors of sustained virological response to pegylated interferon/ribavirin therapy in chronic hepatitis c infected Egyptian patients in the Northeast Provinence. Med J Cairo Univ 2012; 80
Torres FJ, Rodriguez-Torres M, Rockstroh JK, Lazzarin A, Sette H, Passe S, et al.
Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351
Ismail HM. Predictors of sustained virological responses to combination therapy of pegylated interferon-alpha and ribavirin in patients with chronic hepatitis C infection. J Family Community Med 2013; 20
De Carega BO. Predictor factors for response to treatment of chronic hepatitis C. J Hepatol 2006; 5
Elgouhari EM, Zein CO, Zein NN, Feldstein E, Hanouneh I. Diabetes mellitus is associated with impaired response to antiviral therapy in chronic hepatitis C infection. Dig Dis Sci 2009; 54
Ascione A, Deluca M, Tartagline MT, Lampasi F, Giuseppe G, Leandro G, et al.
Peginterferon alfa-2a plus ribavirin is more effective than peg-interferon alfa-2b plus ribavirin for treating chronic hepatitis C virus infection. Gastroenterology 2010; 13
Kamal SM, El Kamary SS, Shardell MD, Hashem M, Mansour H, Moustafa A, et al.
Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virological response. Hepatology 2007; 46
Kamal SM, El-Tawil AA, Nakalo T, Rasenack J, Ismail A, Aziz AA, et al.
Peg-interferon α-2b and ribavirin therapy in chronic hepatitis C genotype 4: impact of treatment duration and viral kinetics on sustained virological response. Gut 2005; 54
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]